Autoantibodies contribute to the immunopathogenesis of experimental dry eye disease

• Published in: Investigative ophthalmology & visual science 2012-04, Vol.53 (4), p.2062-2075
• Main Authors: Stern, Michael E, Schaumburg, Chris S, Siemasko, Karyn F, Gao, Jianping, Wheeler, Larry A, Grupe, Devin A, De Paiva, Cintia S, Calder, Virginia L, Calonge, Margarita, Niederkorn, Jerry Y, Pflugfelder, Stephen C
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Autoantibodies - blood; Autoantigens - immunology; Blotting, Western; CD4-Positive T-Lymphocytes - immunology; Complement Activation - immunology; Complement C3b - metabolism; Disease Models, Animal; Dry Eye Syndromes - immunology; Dry Eye Syndromes - pathology; Female; Fluorescent Antibody Technique, Indirect; Immunity, Humoral - physiology; Immunization, Passive; Immunoglobulin G - immunology; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Tissue Kallikreins - immunology
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.11-9299

The purpose of this study was to determine if autoantibodies play a role in the immunopathogenesis of experimental dry eye disease. Dry eye was induced by exposing female C57BL/6 wild-type mice or hen egg lysozyme B-cell receptor transgenic mice to desiccating stress (subcutaneous scopolamine [0.5 mg/0.2 mL] 3 times a day, humidity < 40%, and sustained airflow) for 3 weeks, allowing sufficient time for a humoral immune response. Serum or purified IgG isolated from dry-eye mice or untreated controls was passively transferred to nude recipient mice, which were evaluated for ocular surface inflammation 3 days after transfer. To determine if complement activation contributed to serum-induced dry eye disease, cobra venom factor was used to deplete complement activity. Autoantibodies against kallikrein 13 were identified in serum from dry-eye mice, but were undetectable in untreated controls. Autoantibody-containing serum or purified IgG from dry-eye mice was sufficient to mediate complement-dependent ocular surface inflammation. Serum or purified IgG caused marked inflammatory burden and tissue damage within the ocular surface tissues, including elevated Gr1+ neutrophil infiltration and proinflammatory cytokines/chemokines associated with goblet cell loss. Moreover, complement C3b deposition was found within the ocular surface tissues of mice receiving dry-eye serum, but not in recipients of control serum. Functionally, complement depletion attenuated the ability to transfer dry-eye-specific serum or IgG-mediated disease. These data demonstrate for the first time a complement-dependent pathogenic role of dry-eye-specific autoantibodies, and suggest autoantibody deposition within the ocular surface tissues contributes to the predominantly T-cell-mediated immunopathogenesis of dry eye disease.